Antibiotics cytotoxic

The marine cytotoxic antibiotic (R)-(-)-dysidazirine (286 Scheme 3.102) was prepared for the first time by Davis and co-workers from N-sulfinylaziridine 244 [95]. Treatment of N-sulfmylaziridine 244 with LDA at -95 °C in the presence of TMSC1 afforded 286 in 62% yield [95]. 

The first compound is an antibiotic isolated from Streptomyces aureus [20], while the second compound is a cytotoxic antibiotic isolated from Dysidea fragilis, a marine sponge [21]. A logical approach to the synthesis of azirines would be an elimination reaction of a suitably M-substituted aziridine. Thus, AT-chlorination of aziridine-2-carboxylic esters was carried out using ferf-butyl hypochlorite (Scheme 8). 

Haliclonacyclamine F (25), arenosclerin D (26), and arenosclerin E (27) have been recently isolated from the sponge Pachychalina alcaloidifera endemic in Brazil [26]. The alkaloids 25-27 were isolated from the cytotoxic, antibiotic, and antituberculosis MeOH crude extract of P. alcaloidifera by a series of separations on silica-gel and cyanopropyl-bonded silica-gel columns. The structures of compounds 25-27 were established by the same approach employed for the structural elucidation of haliclonacyclamine E (13) and arenosclerins A-C (14-16) [18], as well as by comparison with NMR data for this last series of alkaloids. The alkaloids 25-27 displayed moderate cytotoxic activity against SF295 (human CNS), MDA-MB435 (human breast), HCT8 (colon), and HL60 (leukemia) cancer cell lines. 

Similar to the Pd-catalyzed pyrrole and thiophene annulations, an intramolecular Heck reaction of substrate 91 resulted in benzofuran 92 [80], Such an approach has become a popular means of synthesizing fused furans. Muratake et al. exploited the intramolecular Heck cyclization to establish the tricyclic core structure en route to the synthesis of a furan analog of duocarmycin SA, a potent cytotoxic antibiotic [81]. Under Jeffery s phase-transfer catalysis conditions, substrate 93 was converted to tricyclic derivatives 94 and 95 as an inseparable mixture (ca. 4 1) of two double bond isomers. 

Q84 Paclitaxel is a cytotoxic antibiotic. Paclitaxel is used in primary ovarian cancer. 

Ciclosporin, a calcineurin inhibitor, is a potent immunosuppressant useful in the prevention of rejection in organ transplants and grafting procedures. Ciclosporin is markedly nephrotoxic. Vincristine is a vinca alkaloid cytotoxic agent fluorouracil and methotrexate are both antimetabolite cytotoxic agents and bleomycin is a cytotoxic antibiotic. 

Various cytotoxic antibiotics bleomycin sulfate mitomycin mitotane... 

III. Cytotoxic antibiotics Dactlnomycln (Actlnomycln-D) (COSMEGEN) 15 pg/kg IV daily for 5 days... 

The anthracycline antibiotics, which include doxorubicin, daunorubicin, bleomycin, and mitomycin C, inhibit DNA and RNA synthesis. Doxorubicin also interfers with topoisomerase II (a DNA gyrase), the activity of which is markedly increased in proliferating cells. Structurally related to doxorubicin are epirubicin and mitozantrone. The cytotoxic antibiotics are used to treat leukaemias and lymphomas and also for solid tumours in the breast, lung, thyroid and ovary. Cardiotoxicity is the major dose-limiting factor, with arrhythmias and myocardial depression (Bacon and Nuzzo 1993). The chronic phase of cardiotoxicity is a dose-dependent cardiomyopathy that leads to congestive heart failure in 2-10% of patients. Myocardial injury is the result of oxygen free radical formation. Children are particularly sensitive to these cardiotoxic reactions and may require a heart transplant in their later years. Epirubicin is less cardiotoxic than doxorubicin. 

Plicamycin is a cytotoxic antibiotic (see Chapter 54) that has been used clinically for two disorders of bone mineral metabolism Paget s disease and hypercalcemia. The cytotoxic properties of the drug appear to involve its binding to DNA and interruption of DNA directed RNA synthesis. The reasons for its usefulness in the treatment of Paget s disease and hypercalcemia are unclear but may relate to the need for protein synthesis to sustain bone resorption. The doses required to treat Paget s disease and hypercalcemia are about one tenth the amounts required to achieve cytotoxic effects. 

The dolabellanes, represented by 3-hydroxydolabeila-4(16), 7, 1 l(12)-triene-3,13-dione 1 and the neodolabellanes, represented by (+)-4,5-deoxyneodolabelline 2, are isolated from both terrestrial and marine sources. They show cytotoxic, antibiotic and antiviral activity. The recent synthesis of (+)-4,5-deoxyneodolabelline 2 by David Williams of Indiana University (J. Am. Chem. Soc. 125 1843,2003) highlights both the strengths and the challenges of the current state of the art in asymmetric synthesis. 

As an extension of this chemistry, 7V-sulfinyl aziridine 188, prepared from (/ )-187, was utilized in the asymmetric synthesis of protein kinase C inhibitor D-e/yf/iro-sphingosine 189" and in the first enantioselective synthesis of the marine cytotoxic antibiotic (/ )-(-)-dysidazirine (190).100 This latter result constitutes the first general method for preparing nonracemic 2//-azirines, the smallest of the unsaturated nitrogen heterocycles.100,101... 

Neihumicin, 3,6-dibenzylidene-5-methoxy-3,6-dihydro-2(l//)-pyrazinone, a Mi-cromenospora sp fungus metabolite a cytotoxic antibiotic [111451-12-8].1156... 

Alkylating agents Anti metabolites Cytotoxic antibiotics Platinum drugs Topoisomerase inhibitors... 

Cytotoxic antibiotics depress the bone marrow, cause gastrointestinal upsets and stomatitis, alopecia, cardiomyopathy (daunorubicin and doxorubicin) and pulmonary fibrosis and skin rashes (bleomycin). Some of these effects are dose-dependent, for example, doxorubicin-induced cardiomyopathy. Others may be potentiated by concomitant use of radiotherapy. 

T lymphocytes were also proposed as a potential therapeutic drug carriers for cancer treatment (Steinfeld et al., 2006). The kinetics of loading and release of nanoparticles coated with cytotoxic antibiotic Dox into the cells were examined. It was suggested that the immune cells can accomplish target-specific and sheltered transport to the diseased site. 

Anthracyclines form a broad group of antitumor drugs within the group of cytotoxic antibiotics. The lead compounds were doxorubicin and daunorubicin analogues include epirubicin, idarubicin, and aclarubicin. Mitoxantrone and pixantrone are related compounds of the anthracenedione family. Amsacrine is a related compound of the aminoacridine family. 

Cytotoxic antibiotics produce their effect mainly by direct action on DNA. Anthracyclines include the important drugs doxorubicin, aclarubicin and idarubicin. Related compounds are mitozantrone and epirubicin. Some others are the Streptomyces antibiotic dactinomycin. and the metalchelating glycopeptides especially bleomycins. Mitomycin effectively is a prodrug that is converted in the body to an alkylating agent. 

Mithramycin (plicamycin) is a potent cytotoxic antibiotic that inhibits osteoclast-mediated bone resorption and thereby reduces hypercalcemia. Mithramycin may be administered at a dose of 25 mcg/kg via intravenous infusion over 4 to 6 hours in saline or 5% dextrose solutions. This therapy may be repeated daily for 3 to 4 days or on alternating days for 3 to 8 doses. ° Serum calcium levels begin to fall within 12 hours of a mithramycin dose, with the peak effect generally occurring within 48 to 96 hours.Single doses are usually well tolerated. Adverse effects of mithramycin include nausea, vomiting, stomatitis, thrombocytopenia, inhibition of platelet function, and renal and hepatotoxicity. Because these adverse effects are more commonly associated with multiple doses, mithramycin is usually limited to short-term therapy in patients who have not responded to alternative therapies. Monitoring parameters include complete blood count, liver function, and renal function. Mithramycin should be avoided in patients with thrombocytopenia and liver and renal insufficiency. ... 

Some cytotoxic antibiotics prevent cell division by direct action on DNA. Others form polynucleotides, which inhibit transcription of DNA to RNA and therefore suppress protein synthesis. 

Examples of cytotoxic antibiotics are doxorubicin, dactinomycin and bleomycin. 

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